The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

BMC Psychiatry. 2002 Jul 3:2:8. doi: 10.1186/1471-244x-2-8.

Abstract

Background: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors.

Presentation of the hypothesis: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia.

Testing the hypothesis: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations.

Implications of the hypothesis: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments.

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Brain / growth & development
  • Child
  • Child, Preschool
  • Genetic Linkage
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Humans
  • Models, Genetic
  • Models, Theoretical
  • Neuregulin-1 / genetics
  • Neuregulin-1 / physiology*
  • Neuroglia / physiology
  • Phenotype
  • Risk Factors
  • Schizophrenia / genetics
  • Schizophrenia / physiopathology*
  • Seasons
  • Synapses / genetics
  • Synapses / physiology*

Substances

  • Neuregulin-1